6mdw
Mechanism of protease dependent DPC repair
Structural highlights
DiseaseSPRTN_HUMAN Progeroid features-hepatocellular carcinoma predisposition syndrome. The disease is caused by mutations affecting the gene represented in this entry. FunctionSPRTN_HUMAN Regulator of UV-induced DNA damage response: acts as a 'reader' of ubiquitinated PCNA that enhances RAD18-mediated PCNA ubiquitination and translesion DNA synthesis (TLS). Recruited to sites of UV damage and interacts with ubiquitinated PCNA and RAD18, the E3 ubiquitin ligase that monoubiquitinates PCNA. Facilitates chromatin association of RAD18 and is required for efficient PCNA monoubiquitination, promoting a feed-forward loop to enhance PCNA ubiquitination and translesion DNA synthesis. Acts as a regulator of TLS by recruiting VCP/p97 to sites of DNA damage, possibly leading to extraction of DNA polymerase eta (POLH) by VCP/p97 to prevent excessive translesion DNA synthesis and limit the incidence of mutations induced by DNA damage.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedThe DNA-dependent metalloprotease Spartan (SPRTN) cleaves DNA-protein crosslinks (DPCs) and protects cells from DPC-induced genome instability. Germline mutations of SPRTN are linked to human Ruijs-Aalfs syndrome (RJALS) characterized by progeria and early-onset hepatocellular carcinoma. The mechanism of DNA-mediated activation of SPRTN is not understood. Here, we report the crystal structure of the human SPRTN SprT domain bound to single-stranded DNA (ssDNA). Our structure reveals a Zn(2+)-binding sub-domain (ZBD) in SprT that shields its active site located in the metalloprotease sub-domain (MPD). The narrow catalytic groove between MPD and ZBD only permits cleavage of flexible substrates. The ZBD contains an ssDNA-binding site, with a DNA-base-binding pocket formed by aromatic residues. Mutations of ssDNA-binding residues diminish the protease activity of SPRTN. We propose that the ZBD contributes to the ssDNA specificity of SPRTN, restricts the access of globular substrates, and positions DPCs, which may need to be partially unfolded, for optimal cleavage. Structural Insight into DNA-Dependent Activation of Human Metalloprotease Spartan.,Li F, Raczynska JE, Chen Z, Yu H Cell Rep. 2019 Mar 19;26(12):3336-3346.e4. doi: 10.1016/j.celrep.2019.02.082. PMID:30893605[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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